The main purpose of this study is to find out if radiation to the central nervous system (CNS) can be safely omitted with early intensification of chemotherapy and chemotherapy given directly to the CNS. Another purpose is to find out if survival of children with ALL can be improved with risk-directed therapy given on this protocol.

To estimate the overall event-free survival of patients treated with risk-directed therapy

To identify the plasma methotrexate (MTX) concentrations that produce maximum intracellular accumulation of active metabolites (methotrexate polyglutamates, MTXPG) in vivo, in relation to major cell lineage and genotype

To determine the relation between MTXPG accumulation in leukemic lymphoblasts and antileukemic effects, as measured by the inhibition of de novo purine synthesis, and by the decrease in circulating blasts during the 4 days after initiation of single-agent high-dose methotrexate treatment

To determine if plasma MTX concentrations exceeding those required for maximum MTXPG accumulation cause a paradoxical decrease in the accumulation of long-chain MTXPG in lymphoblasts, (e.g., due to "feedback inhibition" of folypolyglutamate synthetase)

To determine if there are significant differences in lymphoblast uptake of MTX and expression of the reduced folate carrier in T-lineage vs B-lineage lymphoblasts, and in hyperdiploid vs non-hyperdiploid B-lineage lymphoblasts

To investigate whether or not the administration of G-CSF at the onset of febrile episodes in neutropenia patients after induction or any of the two reinductions will affect the extent and duration of fever.

To determine whether levels of minimal residual disease in peripheral blood (PB) reflect those measured in the bone marrow (BM) by immunologic or molecular techniques

To assess the degree of DNA damage in somatic cells (leukocytes) during treatment

To explore whether the development of anti-asparaginase antibodies or CSF depletion of asparaginase is correlated with acute toxicities and long-term outcome

To assess the relation between MRI changes of brain (especially white matter abnormalities) from HDMTX and intrathecal treatment, neurologic and cognitive deficits, CSF levels of homocysteines and diminished quality of life

To investigate whether early MRI changes are related to late MRI abnormalities, neurologic and cognitive deficits, and diminished quality of life

To correlate changes in MRI, neurologic or cognitive deficits and diminished quality of life with selected pharmacokinetic variables

To determine the prevalence of low bone density and to correlate this complication with potential risk factors

Details of Treatment Interventions:

Treatment will consist of three main phases, Remission Induction (including an Upfront HDMTX Window), Consolidation, and Continuation.

Window Therapy Upfront HDMTX is considered the first part of remission induction treatment. HDMTX will be given by vein over 24 hours (one day). MTX 500 mg/m2 for standard risk and 250 mg/m2 for low-risk cases will be given over 1 hour, followed immediately by maintenance infusion (4500 mg/m2 for standard/high-risk or 2250 mg/m2 for low-risk cases) over 23 hours.

Triple intrathecal chemotherapy (MHA) is used for the remaining treatment with dosages based on age Frequency and total number of triple intrathecal treatment for Remission Induction are based on the patient's risk of CNS relapse.

Consolidation (2 weeks) Patients receive High dose Methotrexate (HDMTX) 2.5 gm/m2 (low-risk) or 5 gm/m2 (standard-or-high-risk) IV over 24 hr days 1 and 8 and 6-Mercaptopurine 25 mg/m2/day PO days 1 to 14. All patients will receive triple intrathecal therapy weekly for two doses on Days 1 and 8.

Continuation treatment (120 weeks for girls and 146 weeks for boys) Post-remission continuation treatment begins 7 days after the second course of HDMTX of the consolidation treatment, provided that the ANC ≥300/mm3 and platelet count ≥ 50 x 109/L. Continuation treatment will be 120 weeks for girls and 146 weeks for boys and differs according to the risk classification.

Reinduction Treatment This phase of treatment will be started at weeks 12 and 28 after bone marrow examination confirms complete remission.

Reinduction treatment will be given twice:

Weeks 12 to 16 and week 28 to 32 for standard/high risk cases; weeks 12 to 15 and weeks 28-31 for low-risk cases. Leucovorin rescue (5 mg/m2) will be given at 24 and 30 hours after the intrathecal treatment during both remission reinduction treatments. No chemotherapy will be given weeks 16 and 32 for standard/high risk patients.

Hematopoietic Stem Cell Transplantation Patients who meet the criteria of high-risk ALL will be offered the option of transplantation with a matched, related or unrelated donor. However, if the option is declined or if a suitable donor is not available, the patient will remain on study and continue to receive chemotherapy.

One week or less of prior therapy, limited to glucocorticoids, vinca alkaloids, emergency radiation therapy to the mediastinum and one dose of intrathecal chemotherapy Exclusion Criteria

Participants greater than 18 years of age

Contacts and Locations

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To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00187005